This Web Page is for summaries of the 2 monthly Concord Dependency Seminars held in Western Sydney between 1999 and 2010. From January 2011 these seminars have transferred to Royal Prince Alfred Hospital and are convened by Dr Richard Hallinan and Prof Paul Haber.

8 August 2009

Mechanisms and Treatment of Alcohol Dependence and its Sequelae: a 2009 Update

Dr Saunders used a single, complex case of alcohol dependence to introduce an overview of neurobiological mechanisms underlying the development of dependence; and a case of fetal alcohol syndrome, as an example of alcohol related neurodegeneration.

Patient K was a woman in her early 40s who had lost a promising professional career and marriage in her late 20s after a severe neurological insult left her with cognitive impairment, gait disturbance and dysarthria. Five years later she had married again and entered into a new phase of life, but gradually developed alcohol dependence with regular consumption of 120-180g/day. Among risk factors were a family history (father) of alcoholism, and the trauma and loss resulting from her disability and possibly also the brain injury itself. Treatment followed a not unusual course of withdrawal management followed by periods of abstinence supported by acamprosate and/or naltrexone, each time with subsequent relapse.

Twin studies show about 50% of population variance of alcoholism to be genetic; there is a tendency to father-son and mother-daughter vectors. Cohort longitudinal studies point to developmental factors especially childhood abuse, be it physical, sexual, or repeated mental abuse, along with other trauma, for example PTSD. At a sociological / anthropological level, cultural, socioeconomic and regulatory factors are also important.

What are the mechanisms of dependence? While workers in the field of addiction are becoming fairly familiar with the idea of meso-limbic reward pathways, our speaker gave us a more comprehensive understanding of the neurobiological mechanisms of dependence by including also mesolimbic stress, and frontal inhibitory, control systems.

Among the neuronal reward circuits, dopaminergic pathways are especially important for psychostimulants and nicotine, and opioid pathways for alcohol and opioids. When such substances are repeatedly or continuously used, the natural activity of these systems is suppressed. A negative mood and motivational state develops: more and more of the substance is required merely to maintain the normal state, while other normally "rewarding" activities become blunted. The substance use can be said to have “high-jacked” the reward system.

At the same time, with repeated substance use the balance is re-set between brain stress and anti-stress systems, through stimulation of pathways involving the excitatory neurotransmitter glutamate and CRF (corticotrophin-releasing factor) and suppression of GABA and ‘Neuropeptide Y’ circuits. The stress systems become “supercharged” to respond to exposure to psychoactive substances and cues or trigger for the substance use.

Finally, with repeated substance use there is progressive impairment of pre-frontal-mesolimbic inhibitory pathways, with impairment of executive functioning, decision-making and insight.

In combination, suppression of reward systems, their "high-jacking” by substance use, and “supercharging” of the stress systems to respond to psychoactive substances and their associated cues, generate a powerful “internal driving force” which is little influenced by voluntary control, because of impaired frontal inhibitory systems.

At this Concord Seminar, when an audience member asked about the situational and emotional triggers for alcohol use in patient K, Dr Saunders responded: "It doesn't matter what the triggers are, she is dependent. There is an overwhelming, tsunami-like force driving it."

Pharmacotherapies for alcohol dependence, included much the same list as when Dr Saunders last spoke to us in 2005, though the evidence base has developed since then.

 Naltrexone (blocks opioid pathways for alcohol reinforcement/reward; see below) Acamprosate (restores balance to GABAergic/glutaminergic stress responses; see below) Topiramate (similarly, restoring balance to GABAergic/glutaminergic pathways in the corticomesolimbic system; several randomised trials from USA, and Finland) Disulfiram (aversive agent, unpleasant reaction on alcohol ingestion; see below) Ondansetron (selective 5-HT(3) (serotonin) antagonist [‘Zofran’] may be effective for patients with early-onset alcoholism, associated with greater serotonergic abnormality & greater mood disturbance, including depression, anxiety, hostility and antisocial behaviors) Baclofen (GABA-B receptor agonist, reducing craving and alcohol intake in small trials) Buspirone (for alcohol dependence and comorbid social anxiety) SSRIs (for underlying or residual depression, and to be avoided in young alcoholic men with depression/suicidality, in whom they may make matters worse – the reason for this is not entirely clear, but see ondansetron above)

While a Cochrane review (Srisurapanont et al, 2005) for naltrexone gives clear evidence that relapse into alcohol dependence is reduced by some 36%, the Cochrane review of acamprosate has not yet reported, and there have been negative findings from recent US and Australian studies. There have been two important studies of combined naltrexone and acamprosate for alcohol dependence, with some evidence of benefit from the combination in Kiefer et al (2003) but little at all for acamprosate from the COMBINE Study (eg Anton et al 2006; Donovan et al 2008). There is also good evidence for improved outcomes for disulfiram, provided it is supervised.

With huge variability in findings from different studies, especially for acamprosate, Dr Saunders notes that exploring the heterogeneity of these studies may be a key for furthering our understanding and planning further research. Much may be lost by the reductionism of meta-analysis. Meanwhile, naltrexone tends to be his first line choice for alcohol dependence.

Some basic contrasts between the use of naltrexone and acamprosate are listed here.

Initiation: for naltrexone, when abstinent or when drinking; for acamprosate only when abstinent. Onset of action: for naltrexone within 24 hours; for acamprosate one weekPattern of drinking: for naltrexone, alcohol dependence with binge pattern; for acamprosate, alcohol dependence with regular daily drinkingTriggers to drink: for naltrexone, smell, taste, initial consumption of alcohol; for acamprosate, geographical, interpersonal and emotional triggersSub-type of dependence: for naltrexone, early onset & strong family history; for acamprosate, later onset. Genetic markers: for naltrexone, having opioid receptor gene (OPMR1- Asp40 allele)

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We were then introduced to a difficult clinical situation. An addiction specialist noticed by chance, while treating a pregnant alcoholic woman abstinent in early recovery, that a previous child had previously unrecognised fetal alcohol syndrome. Ethical issues about contacting that child’s doctor, or community services, the potentially devastating impact of informing this woman at such a time and almost certainly precipitating relapse and worse outcomes led to lively discussion. Happily in this case the fine line was successfully trod.

Fetal Alcohol Syndrome is at the most severe end of the range of Fetal Alcohol Disorder Spectrum (FASD). The features are 1. maldevelopment of the mid face, including a small flattened nose, wide-set eyes, epicanthic folds, a thin upper lip, and absent philtrum2. microcephaly, mental retardation (average IQ 70) and behavioural abnormalities3. congenital cardiac abnormalities

Learning difficulties become apparent in childhood, and there is no improvement in IQ over time. There are social interaction deficits, but more typically the children are over-friendly to peers and adults, and so-called moral deficits – high prevalence of promiscuity, sexually transmitted diseases in teen years - may be attributable to these factors.

Management consists of teaching adaptive living skills, (such as to be appropriately guarded with strangers and certain family members), educational placement, speech and language services, occupational therapy and vocational guidance, and advocacy as needed.

This brought us to the matter of alcohol and neurodegeneration, especially in young people. We are reminded that brain development continues until at least the age of 21. Particularly that during this time, but also afterwards, neurones and their connections are in a state of dynamic flux, of which ongoing neurogenesis is an essential part.

In experimental animals, with increasing alcohol exposure there is increased differentiation of neural stem cells to oligodendrocytes and astrocytes and reduced differentiation to neurones, with blunting of dendrites, and inhibition of neurogenesis as a primary mechanism of neurodegeneration. In Fetal Alcohol Syndrome there is not only major structural damage in the 1st trimester but a quantitative decline in the number of neurones in the 3rd trimester through inhibition of neurogenesis (in which tobacco smoking, diet and vitamin deficiencies probably also play a role).

Also, Dr Saunders won't mind us giving a plug for a new "concise and practical guide for students and practitioners of medicine and other health professions who come into contact with people with substance use disorders." Addiction Medicine. Editors Noeline Latt, Katherine Conigrave, Jane Marshall, John Saunders, E. Jane Marshall and David Nutt. Oxford University Press. ISBN13: 9780199539338

Disclaimer

On this web site, Dr Byrne and colleagues have written summaries of many research articles, conferences and other events. These have been written largely to draw attention to peer-reviewed studies which may be relevant to clinical practice and public policy. While all care has been taken to be fair and accurate, readers are strongly advised to read the original publications before acting upon the information for clinical decisions.

Due to this brief form of communication, no responsibility can be taken for errors, mistakes or omissions.